While sub-Saharan Africa is home to 10% of the world's population, 90% of the world's HIV-infected children live in the region. The majority of these (16% or 280,000) live in South Africa, where HIV/AIDS accounts for 57% of deaths in children below 5 years of age. With improving access to antiretroviral treatment (ART), the disease is changing from fatal to chronic. However, central nervous system penetration by ART is limited and the brain is a reservoir for the virus, with dramatic consequences to the developing fetal/child brain. The Children with HIV early antiretroviral therapy (CHER) project is supported by the Comprehensive International Program for Research on AIDS in South Africa (CIPRA-SA), and has been following a cohort of children born with HIV. Controls were recruited by an interlinking vaccine trial supported by CIPRA-SA. This is a unique and extremely well characterized cohort of children in three treatment arms in which ART (1) was delayed until immunological/clinical criteria were met, (2) commenced before 12 weeks and was interrupted after 40 weeks and (3) commenced before 12 weeks and was interrupted after 96 weeks. After two years, results showed that early HIV diagnosis and ART reduced early infant mortality by 76% and HIV progression by 75%. In an addendum to the study, Dr. Barbara Laughton performed comprehensive neuropsychological testing on the Cape Town participants. The study will end after all children reach 5 years of age in June 2011. Studies of neurodevelopment in children with HIV in developing countries are rare and brain imaging studies of young children with HIV anywhere in the world are also scarce. Longitudinal brain imaging studies in children with HIV are non-existent. We have completed cognitive testing and MR imaging in a subset of the 210 children in the Cape Town branch of the CHER cohort at the age of 5 years. Imaging was done at the Cape Universities Brain Imaging Center (CUBIC), using motion-corrected brain morphometry, spectroscopy and diffusion tensor imaging protocols that were developed jointly by our groups. This facility houses a state- of-the-art research-dedicated Siemens 3 T Allegra MRI scanner optimized for brain imaging and is unique in sub-Saharan Africa. In this project, we will follow the children further with comprehensive neuropsychological testing and brain imaging at the ages of 7 and 9 years. The multi-time point longitudinal data will give us greater power to assess how cognitive and anatomical development proceeds in healthy children between 5 and 9 years and how this is affected by HIV infection and treatment with ART. We hope that our findings will help to guide treatment even in resource-poor environments where imaging may be unavailable. This project builds on a successful collaboration between Dr. Barbara Laughton (Stellenbosch University), Dr. Ernesta Meintjes (University of Cape Town) and Dr. Andri van der Kouwe (Massachusetts General Hospital). The project will build capacity including analysis methods for longitudinal data and advanced image acquisition techniques in young children, without the risk of sedation or anesthesia.